tbuckley/cabot-search huggingface dataset:
Abstract 12041: Tyrosine Kinase Inhibitors Leads to Sodium Channel Dysfunction in the Heart
Authors: Ashley Greenlee, Ethan Schwendeman, Shane Scott, Hassan Musa, Matthew Stein, Divya Patel, Somayya Mohammad, Sakima A Smith
Journal: Circulation (2022)

Tyrosine Kinase Inhibitors (TKIs) are used by tens of thousands of patients and are efficacious for treating renal cell carcinoma . However, TKIs have been reported to have numerous off-target effects, including arrhythmias and heart failure. Many patients who receive TKIs are over 60 years of age and have existing cardiac diseases, thus increasing their risk of cardiotoxicity. However, the exact mechanism to how these TKIs cause cardiotoxicity remains unclear. Our research goal is to understand how TKIs lead to cardiotoxicity by learning what proteins are being targeted and what are potential upstream regulators so we can introduce possible treatments that can combat these effects. Recent literature has stated that the TKI Sorafenib led to increased reactive oxygen species (ROS) production and Calcium (Ca 2+ )/Calmodulin dependent kinase II (CaMKII) activity in rat ventricular cardiomyocytes. ROS can activate CaMKII, and increased CaMKII activity can lead to hyperphosphorylation of the voltage-gated sodium channel, leading to pathophysiological enhancement of late sodium current (I Na,L ). Increased activity of CaMKII and I Na,L can be seen in arrhythmias and heart failure. We hypothesize that TKIs lead to an increase enhancement of I Na,L due to an increase in ROS production and increased CaMKII activity. To test this hypothesis, we treated H9c2 myoblasts with Pazopanib (n=3) or DMSO (n=3) and wild-type mice with Pazopanib (n=5) or DMSO (n=5). After treatment, we assessed cytosolic and mitochondrial ROS production in vitro and functional affects, CaMKII activity, and I Na,L current in vivo . Results showed that Pazopanib led to a significant increase in ROS production in H9c2 cells and more arrhythmogenic events in WT mice. While CaMKII activity or I Na,L expression was not significantly changed between the two groups, with electrophysiology studies Pazopanib did lead to alterations in amplitude, peak current, ultra-slow inactivation, and recovery. In conclusion, Pazopanib leads to cardiovascular dysfunction and this could be due to an increase in ROS production and altered sodium channels. Our study indicates a potential mechanism as to how TKI treatment leads to cardiotoxicity in patients.
Abstract 12532: Impact of Autoimmune Hepatitis on Mortality and Outcomes of Hospitalized Patients Presenting Non-st-Segment Elevation Myocardial Infarction
Authors: Olukayode Busari, Michael Fatuyi, Emmanuel Akuna
Journal: Circulation (2022)

Introduction: Autoimmune hepatitis (AIH) is an inflammatory chronic liver disease disease when one’s immune system attacks the liver. Due to the widespread inflammatory response, we sought to evaluate the association between Autoimmune Hepatitis and mortality in patients hospitalized with Non-ST-Segment Elevation Myocardial Infarction (NSTEMI). Methods: Patients hospitalized for NSTEMI with and without AutoImmune Hepatitis between 2016 to 2018 were identified from the National Inpatient Sample. The primary outcome was all-cause mortality. The secondary outcomes were; Length of stay, total hospital charge and odds of requiring intra aortic balloon pump. A multivariable logistic regression analysis was used to adjust for in-hospital complications. A p-value of &lt;0.05 was considered significant. Results: There were a total of 949,984 NSTEMI patients. Out of this number, 949,659 patients had NSTEMI without AIH, while 324.9 had NSTEMI with AIH. The mean age for NSTEMI without AIH was 68.2 years while the mean age for NSTEMI with AIH was 68.7 years. The odds of in-patient mortality in NSTEMI without AIH vs NSTEMI with AIH was 3.46% vs 4.62% respectively, (aOR= 1.5 , CI = 0.505 - 4.696, p = 0.76). The length of hospital stay (LOS) in NSTEMI without AIH vs NSTEMI with AIH was 4.58 days vs 4.66 days respectively, (CI = -1.016 - 1.223, P=0.18); and total hospital charges (THC) were $86,631 vs $81,851, ( CI = -23814 - 20432, P = -0.15). The odds of requiring intra aortic balloon pump (IABP) between NSTEMI without AIH vs NSTEMI with AIH was 2.49% vs 1.54% respectively, (aOR = 0.72, CI = 0.101 - 5.177). Conclusions: Patients with AutoImmune Hepatitis in the setting of NSTEMI did not have a difference in mortality or other clinical outcomes when compared with patients without AutoImmune Hepatitis. As with most observational studies, causality may not be confirmed due to potential residual confounding.
Abstract 11544: Prognostic Risk Stratification of Cardiac Metastasis via Quantitative Perfusion Cardiac Magnetic Resonance Imaging
Authors: Christine Park, Tania Ruiz Maya, Katherine Tak, Jiwon Kim, Richard Steingart, Jonathan W Weinsaft, Angel T Chan
Journal: Circulation (2022)

Introduction: Cardiac magnetic resonance (CMR) is widely used to assess cardiac masses, including cardiac metastases (C MET ). Perfusion CMR can quantify magnitude of tumor vascularity; prognostic relevance of lesion perfusion among patients (pts) with C MET is unknown. Methods: The population comprised adult cancer pts with C MET and controls matched for cancer type/stage. Late gadolinium enhancement (LGE) CMR was the reference for C MET . Perfusion CMR quantified vascularity within lesions, including contrast enhancement (CER: maximum vs. baseline) and uptake (CUR [slope] ratios during gadolinium infusion (0.1mmol/kg). Follow-up was performed for mortality. Results: 155 C MET pts (59 ± 15yo, 56% male) and cancer matched controls underwent CMR, including a range of primary cancers (sarcoma 22%, GU 17%, GI &amp; lung 12%). Anti-cancer treatment, cardiac risk factors and LVEF were similar between groups (p=NS). In relation to LGE-CMR, perfusion yielded good performance to distinguish C MET (AUC 0.57-0.97; p &lt; 0.001). During follow-up, C MET pts tended to have higher aggregate 1 year mortality vs. controls (56% vs. 46%; p=0.09); median time to death was 6.8 (2.5, 17.1) months post-CMR. Pts with C MET on perfusion CMR had higher mortality risk than controls (HR 1.41 [1.04-1.92], p=0.03), paralleling LGE-CMR (HR 1.52 [CI 1.14-2.02], p=0.004). C MET mortality increased stepwise with impaired perfusion (Figure A) and was highest among pts in the bottom (vs. top) CER tertile, corresponding to decreased tumor vascularity. Among cancer matched subgroups, pts with C MET in the bottom CER tertile had higher mortality than controls (p &lt; 0.001); prognosis was equivalent to controls (p=NS) among pts with lesions in the highest two CER tertiles (Figure B). Conclusions: Perfusion CMR identifies CMET based on vascularity and stratifies prognosis: Among cancer pts with CMET on LGE, mortality increases in proportion to magnitude of decreased tumor vascularity on perfusion CMR.
Abstract 12471: Ventricular Tachycardia Ablation vs Antiarrhythmic Drug Efficacy and Safety: A Meta-Analysis and Systematic Review of Randomized Studies
Authors: Muzzamal Habib, Cian Lolait, Usama Boles, Katie A Walsh, Gerard J Fahy, Edward Keelan, G. Muqtada M Chaudhry, Joseph Galvin
Journal: Circulation (2022)

Introduction: Ventricular tachycardia (VT) poses a significant risk in patients with ischemic cardiomyopathy. Antiarrhythmic drugs (AAD) and catheter ablation are the 2 strategies employed to reduce the risk of future VT episodes. It is not established if one strategy is superior to the other. Hypothesis: Recently, randomized trials have been published comparing the efficacy and safety of both strategies for VT management. Unfortunately, most of these trials included a relatively small number of patients and had different outcomes or composite of outcomes limiting their utility. Methods: We performed a meta-analysis of randomized clinical trials comparing these treatment modalities for VT management. Criteria for appropriate studies were the inclusion of outcome data for both ablation and AAD arms, history of documented VT or ICD therapy before enrollments, and use of ICD to reliably monitor the incidence. Due to recent advances in substrate-based VT ablation and changes in ICD algorithms we limited our search for studies published in last 10 years. We identified four studies that met our inclusion and exclusion criteria. Results: Our included studies randomized 609 patients, 303 in ablation, and 310 in AAD groups. All-cause mortality data were available for all included studies. The cumulative odds ratio (OR) for all-cause mortality for VT ablation compared to AADs was 0.88, 95% confidence interval [0.56-1.39], p-value 0.58. Cumulative OR for cardiac death was 0.81 [95% CI 0.47-1.38], p-value 0.44, OR for ICD shocks was 0.82[0.57-1.18], p-value 0.29 and the OR for heart failure or cardiac rehospitalization was 0.82 [95% CI 0.53-1.25] p-value 0.35. Treatment-related complications were reported in only two studies with cumulative OR 0.31 [95% CI 0.19-0.51] p &lt;0.00001. Studies used different definitions of treatment related complications. Conclusions: VT ablation and antiarrhythmic drugs appear to be equally effective treatment strategies to prevent all-cause death, cardiac death, heart failure rehospitalization, and ICD shocks but there is a trend towards better results for all stated outcomes with ablation. There was statistically significantly lower incidence of the reported treatment-related complications with ablation compared to AADs.
Abstract 12529: Left Ventricular Gene Expression Heterogeneity in a Mouse Model of Dyssynchronous and Resynchronized Heart Failure
Authors: Karin Ljung, Eric Rullman, John Pernow, Hugo Nordin, Christian Vestman, Frieder Braunschweig, Ryo Nakagawa, David A Kass, Marcus Stahlberg
Journal: Circulation (2022)

Introduction Cardiac resynchronization therapy improves the prognosis for patients with heart failure and left bundle branch block through cardiac reverse remodeling. The biological mechanisms governing this process remain largely unknown. In a canine model, it has been shown that dyssynchronous heart failure (DHF) induces regional heterogeneity in left ventricular gene expression which is reversed with resynchronization. We developed a mouse model of dyssynchrony and resynchronization and here use this model to test the hypothesis that DHF induces increased intra left ventricular heterogeneity in gene expression that is ameliorated with resynchronized heart failure (RHF). Methods Heart failure was induced in mice through ischemia/reperfusion. All mice were implanted with a custom-made pacemaker. In the synchronous HF (SHF) group the pacemaker was turned off. In the DHF group the mice received right ventricular pacing (RVP) for four weeks. In the RHF group mice received RVP for two weeks, after which the pacemaker was turned off for two weeks. Heart tissue from the septum and lateral left ventricular wall was subjected to RNA sequencing. Results The expression of 1923 genes differed significantly between early- and late activated left ventricular segments in DHF reflecting regional heterogeneity in gene expression, this disparity was not found in SHF or RHF hearts (Figure A). Figure B shows the ten most significantly upregulated gene ontology (GO) pathways in the lateral wall compared to septum in DHF. These pathways were predominantly associated with cell motility and extracellular matrix processing. Conclusions DHF induces a change in gene expression between the left ventricular septum and lateral wall. This difference is absent in SHF and RHF. Our findings support that resynchronization causes a reversal in gene expression from DHF pattern to SHF pattern and may contribute to further understanding of the remodeling process in DHF and how this may be reversed.
Abstract 11583: Impact of Micra Pacemaker Implantation on Echocardiographic Parameters: A Multi-Center Analysis
Authors: Anil Sriramoju, Mostafa Elbanna, Amith Reddy Seri, Mostafa Mahmoud Fahmy, Omar Javed Baqal, Nway KoKo, Hasan Ashraf, Justin Lee, Hicham El Masry
Journal: Circulation (2022)

Introduction: Studies on leadless pacemakers (LP) are very limited and they often fail to reflect real population outcomes. Hypothesis: We sought to evaluate the effect of leadless pacemaker implantation on the echocardiographic parameters including ventricular function and valvular competence. Methods: A retrospective review including 162 patients (81 Micra Leadless pacemaker implant and 81 dual-chamber transvenous pacemakers) from 3 centers were included. Follow-up clinical, echocardiographic, and pacing characteristics were obtained over a median of 14+/-2 months. Results: baseline demographics and clinical characteristics were comparable between the 2 groups including age (78.6+/-9.9, Range 35-95) and gender (49 males, 69.5%). Compared to conventional pacemakers, LP patients had worsening tricuspid regurgitation noted on follow-up echo in 59.3% of patients compared to baseline(P&lt;0.001). This difference was independent of the RV pacing percentage and device location. In addition, LP implantation resulted in a reduction of RV function (P=0.003) and left ventricular ejection fraction (P=0.03). The RV Pacing burden in LP patient patients was not associated with a change in LVEF during the follow-up period (95% CI -0.24, 0.20, p = 0.846). Conclusions: LP therapy is associated with worsening tricuspid valve regurgitation and biventricular dysfunction over a mean 1 year of follow-up. Additional prospective randomized studies are warranted to further evaluate these findings.
Abstract 11764: A Novel Approach for Pre-Implant Endothelialization of Xenogeneic Decellularized Vascular Tissues by Human Endothelial Cells Utilizing Tissue Surface Modification and Dynamic Culture
Authors: WenJin Ho, Hidetoshi Masumoto, Mako Kobayashi, Kozue Murata, Tadashi Ikeda, Yoshihide Hashimoto, Tsuyoshi Kimura, Kenji Minatoya, AKIO Kishida
Journal: Circulation (2022)

Introduction: Autologous grafts for revascularization might be limited due to the quality of vessels. Decellularized xenogeneic vascular grafts potentially substitute for autologous grafts. We have been developing a decellularization method based on high hydrostatic pressure (HHP) which confers highly preserved extracellular structure. For broader application of the HHP-decellularized vascular graft, pre-implant endothelialization of the grafts by human endothelial cells would be anticipated which may prevent clot formation and graft occlusion. Hypothesis: We hypothesized to achieve sufficient ex vivo endothelialization of HHP-decellularized tissues by virtue of chemical endothelial surface modification and dynamic culture recapitulating blood flow. Methods: Thin slices of bovine aortic endothelium were decellularized by HHP. We divided the tissues in 2 groups: coated with E8 fragment of human laminin 411 (hL411) holding high affinity with endothelial cells and coated with gelatin (Gel). We directly seeded human umbilical vein endothelial cells (HUVECs) with a density of 2 х10 6 cells/cm 2 , then divided the tissues in 2 subgroups: dynamic culture (20 cm/s) and static culture. We kept the culture for up to 2 weeks and evaluated the area coverage by staining of live cells by Calcein-AM, histological analysis, and scanning electron microscopy (SEM). We tested clot formation using human whole blood. Results: hL411/dynamic group exhibited significantly higher area coverage compared to those of other groups which almost reached 100% [coverage at 2 weeks: Gel/static vs hL411/static vs Gel/dynamic vs hL411/dynamic: 57.3±4.1 vs 61.3±2.7 vs 74.7±19.9 vs 99.3±0.7 %, p&lt;0.001(vs NC/static), n=6]. Immunostaining for CD31 and SEM revealed sufficient coverage with endothelial cells in hL411/dynamic. Clot formation assay showed lower clot formation in hL411/dynamic group than in hL411/static (p=0.014) and mock without hL411 coating (p=0.006) (n=3). Conclusions: Surface modification of HHP-decellularized xenogeneic endothelial tissues combined with dynamic culture achieved sufficient ex vivo endothelialization accompanied with the prevention of clot formation which would promote the clinical use of endothelialized vascular grafts in the future.
Abstract 11890: Association Between State Marijuana Legalization Policies and Marijuana Use Reasoning Among Adults With Cardiovascular Disease, 2017-2020
Authors: Tarang Parekh, Shubham Lahan, Zulqarnain Javed, Miguel Cainzos Achirica, Khurram Nasir
Journal: Circulation (2022)

Introduction: The rapid adoption of marijuana legalization policies in states has forced clinicians to evaluate the health effects of marijuana due to increased availability; however, little is known about changes in marijuana use among adults with CVD after legalization (medical, recreational, dual) in the US. Methods: Using a sample of 298,651 adults from 2017-2020 survey data from the Behavioral Risk Factor and Surveillance System (BRFSS), we estimated the prevalence of recent (past-month) marijuana use in eleven states among adults with and without CVD by marijuana legalization (ML) status of a state. Multivariate logistic regression models were conducted to examine factors associated with marijuana use by self-reported CVD status. Results: Recent marijuana use was higher among adults with CVD in ML states compared to non-ML states (10.7% vs. 6.4%). The mean days of marijuana use in the CVD cohort in ML-states were 17.2±15.5, and 16.1±13.7 days in non-ML-states. Medical use among CVD adults decreased from 57.4% in 2017 to 47% in 2020. In contrast, dual-use increased from 14.4% in 2017 to 30.9% in 2020. However, trends were different in ML vs non-ML states(Figure). Adults with CVD in ML-states had higher (OR=1.75, p&lt;.001), while in non-ML states had lower (OR=0.81, p&lt;0.05), odds of marijuana use compared to those without CVD in non-ML states (reference group). Among CVD adults who used marijuana, odds of medical use were 85% higher in ML-states (OR=1.85, p&lt;0.05), while more than two-fold for recreational (OR=2.10, p&lt;0.05) and 2.5-fold for dual-use (OR=2.53, p&lt;0.05), than non-ML states. Conclusions: We found a higher prevalence and likelihood of marijuana use in adults with CVD living in legalized vs. non-legalized states, which was not unexpected. However, marginal decline in use for medical reasons in ML states with the increasing prevalence of recreational and dual-use in the CVD population requires greater attention to the risk/benefits of individual preferences.
Abstract 11371: Exacerbation of Pre-Existing Cardiovascular Disease Following COVID-19 mRNA Vaccination
Authors: Anthony Simone, John Herald, Aiyu Chen, Rohith Nayak, Albert Yuh-Jer Shen, Mingsum S Lee
Journal: Circulation (2022)

Introduction: Reactogenicity with systemic reactions including fatigue, fever, and chills have been reported with COVID-19 mRNA vaccination, with the incidence substantially greater after the second dose. Patients with pre-existing cardiovascular disease may be particularly vulnerable to secondary cardiac complications from the proinflammatory cascade and activation of immunogenic pathways in response to mRNA vaccination. This study aims to evaluate the risk of exacerbation of pre-existing cardiovascular disease after COVID-19 mRNA vaccination. Methods: We included individuals aged 18 years or older with a known history of cardiovascular disease who received at least one dose of COVID-19 mRNA vaccine. Cardiovascular hospitalizations were assessed within 30 days of COVID-19 mRNA vaccination. The observed incidence of cardiovascular hospitalization following vaccination or COVID-19 infection was compared with the expected incidence using data obtained from the same population during the same 30-day calendar period two years prior (a baseline period before the COVID-19 pandemic). Odds ratio (OR) and 95% confidence intervals (CIs) were calculated. Results: A total of 229,829 patients were identified as having a history of cardiovascular disease. In this group, 165,711 received at least one dose of COVID-19 mRNA vaccines (39.9% mRNA-1273 and 32.2% BNT162b2), and 160,482 received at least two doses (38.7% mRNA-1273 and 31.2% BNT162b2). The median age was 72 years (interquartile range 62, 80), 42.8% were women, 52.2% White, 25.4% Hispanic, 10.4% Asian, and 10.2% Black. Within 30 days after receiving dose one vaccination, 844 patients were hospitalized for a cardiovascular cause. During a baseline 30-day window, there were 1012 cardiovascular admissions, corresponding to an OR of 0.86 (95% CI 0.76-0.91) after vaccination. After dose two vaccination, there were 812 cardiovascular admissions, compared to 960 at baseline (OR 0.85, 95% CI 0.77-0.93). No cardiovascular hospitalization was observed in patients with a history of myocarditis. Conclusions: In this diverse cohort of patients with a history of cardiovascular disease, there was no increase in the risk of cardiovascular hospitalization after COVID-19 mRNA vaccination.
Abstract 11608: Differences in Genetic Variants and Common Genetic Regulators between Arrhythmogenic Cardiomyopathy and Arrhythmogenic Dilated Cardiomyopathy Identified Using Systems Genetics Approaches
Authors: Buyan-Ochir Orgil, Fuyi Xu, Neely Alberson, Lu Lu, Jeffrey A Towbin, Enkhsaikhan Purevjav
Journal: Circulation (2022)

Introduction: Prominent arrhythmias are features of arrhythmogenic cardiomyopathy (ACM) and arrhythmogenic dilated cardiomyopathy (aDCM). Despite clinicopathological differences, these diseases share common genetic causes. Hypothesis: This study aimed to identify variants in ACM and aDCM and map the candidate genetic regulators using a mouse genetic reference population (GRP). Methods: Whole exome sequencing was performed on 226 individuals with ACM and 102 patients with aDCM. Bioinformatics analysis was applied to identify the pathogenic or likely pathogenic variants followed by direct sequencing confirmation. Expression quantitative trait loci (eQTLs) mapping to heart transcriptomes of GRP of BXD recombinant inbred (RI) mice was conducted in GeneNetwork (http://www.genenetwork.org). Results: In the ACM cohort, a total of 82 variants (MAF&lt;0.01) in 24 genes have been confirmed being positive in 42 probands. Depending on the frequency of the identified variants, the top 10 genes (excluding TTN) with the most pathogenic variants were PKP2, MYH6, FLNC, RYR2, MYH7B, PLEC, JPH2, SYNE1, NRAP and POSTN. In the aDCM cohort, 141 pathogenic variants have been identified and 91 patients harbored at least 1 deleterious variant. The top 10 genes were RYR2, FLNC, MYH7, DSP, SCN5A,MYPN, NEBL, CTNNA3, ACAP6 and SLC22A5. We analyzed the distribution of the first principal component (PC1) of mRNA expression levels of those 10 genes (eigentraits) from each cohort in the heart across BXD strains. Interval mapping for PC1 eigentraits for ACM identified a significant eQTL (P&lt;0.05) in the mouse genome at 24-36 Mb of chromosome (Chr) 6. In aDCM, interval mapping for PC1 eigentraits identified 3 suggestive eQTLs at Chr 5 (44-53 Mb), Chr 6 (32-34 Mb) and Chr 15 (82-84 Mb). Further gene exploration of these eQTLs suggested that Mtpn, Lep, Cyb5r3, Tspo, Slit2, and Ppargc1a could be common regulators that interact with those top ACM and aDCM genes. Conclusions: This study identified diverse genes in ACM and aDCM cases. Our joint human and mouse analysis using a systems genetics approach identified genetic regulators that could affected expression of genes with pathogenic variants in ACM and aDCM patients.